The overall goal of this proposal is to define the role of new putative tumor suppressor gene located at the q23 locus on human chromosome 5 in the development of colon cancer. Lysyl oxidase is a multifunctional, copper-dependent amine oxidase responsible for the development of lysine-derived crosslinks in the extracellular matrix proteins, collagen and elastin. Over the last five years, several groups of investigators, including ourselves, have shown that this enzyme also exhibits a ras-related growth regulatory function. We have recently completed the detailed characterization of the entire human lysyl oxidase gene, including the localization of this gene to the q23 region of chromosome 5 and the identification of two informative polymorphic markers within exon 1 and 10kb upstream of the lysyl oxidase gene. These polymorphisms were used to establish loss of heterozygosity within the 5q23 locus in tumor DNA from approximately 20% of a cohort of 98 patients diagnosed with colorectal cancer. Moreover, in three of these patients, a lysyl oxidase gene mutation was identified in the surviving allele in these tumor DNA samples. This data supports our hypothesis that deletions and mutations at 5q23, involving a new putative tumor suppressor encoded by the lysyl oxidase gene, are involved in the development of colon cancer. This proposal seeks to characterize these 5q23 rearrange- ments in order to begin to understand the role of lysyl oxidase gene mutations in the cascade of genetic events that lead to colorectal tumorigenesis.